Fetrastobart vedotin

辉瑞披露SSGJ-707海外临床方案： 1/ 第一轮近期启动 7 项临床，包括1L NSCLC和1L mCRC的全球3期临床，并预计仅考虑NSCLC和CRC市场，两者的潜在空间达700亿美金和90亿美金，除此之外，近期会启动ES-SCLC 2/3期，NSCLC 1/2期（联用ADC），Ia/mHCC、Ia/mUC、Ia/mRCC 1/2期； 2/ 2026年底前计划启动 10 个额外适应症和 10 种以上新组合疗法的临床试验，覆盖不同治疗阶段、疗法线数及新型组合，并探索更多ADC联用； 3/ 计划入组至少20%以上美国患者，纳入代表性全球患者，充分发挥辉瑞强大全球临床组织协调与肿瘤科资源能力； 4/ 辉瑞制药为707布局了全球500个临床试验中心，有超过50+肿瘤KOL提供内部建议，且目前辉瑞基本完成了707的美国生产布局，将利用全球10个生产基地进行后续生产开发。 Before we kick off the main discussion, I’d like to take a moment to introduce our speaker, Jeff Legos, Pfizer’s Chief Oncology Officer. In addition, Johanna Bendell, Chief Development Officer for Oncology; and Arati Rao, 4404’s franchise head will participate in our Q&A. Jeff, Johanna and Arati, welcome, and thank you so much for joining the conversation today. Jeff, let’s get started. Can you remind us what 4404 is, how it works and how it fits into Pfizer’s broader oncology pipeline and portfolio? 在进入主题讨论之前，请允许我先介绍今天的演讲嘉宾——辉瑞肿瘤业务首席官杰夫·莱戈斯。此外，肿瘤业务首席开发官约翰娜·本德尔以及 4404 项目负责人阿拉蒂·拉奥也将参与问答环节。杰夫、约翰娜和阿拉蒂，欢迎各位的到来，非常感谢你们今天参与讨论。杰夫，现在请您开始。 能否请您简要说明 4404 的定义、作用机制，以及它在辉瑞更广泛的肿瘤研发管线和产品组合中的定位？ Thanks, Francesca. That’s good. Yes. I’m very happy to. 4404 is a bispecific antibody with potential transformative mechanism of action that may enable it to be a foundational therapy across multiple cancers. As shown on the left-hand side of the slide, at the heart of 4404 is its ability to target both PD-1 and VEGF. PD-1 is a key receptor that typically acts to prevent immune cells from attacking cancer cells. VEGF, the other target of 4404 plays an important role in tumor blood vessel formation. We’ve seen that PD-1 and PD-L1 checkpoint inhibitors are amongst the most broadly impactful oncology medicines developed to date. Furthermore, emerging external Phase III data has shown that the combination of PD-1 and VEGF inhibition in a single molecule like 4404 has the potential to achieve superior efficacy versus PD-1 inhibition alone. 谢谢，弗朗西斯卡。很好。是的。 我很乐意。4404 是一种双特异性抗体，其潜在的变革性作用机制可能使其成为多种癌症的基础治疗方案。如幻灯片左侧所示，4404 的核心优势在于同时靶向 PD-1 和 VEGF。PD-1 作为关键受体，通常能阻止免疫细胞攻击癌细胞。 VEGF 作为 4404 的另一靶点，在肿瘤血管生成中发挥关键作用。我们已证实 PD-1 和 PD-L1 检查点抑制剂是迄今最具广泛影响力的抗癌药物。此外，最新 III 期临床数据显示，像 4404 这样单分子同时抑制 PD-1 和 VEGF 的方案，相较于单纯 PD-1 抑制疗法，有望实现更优越的疗效。 If these initial data achieved with PD-1 and VEGF mechanism of action can be proven out in global Phase III studies and in additional treatment settings and tumor types alongside an acceptable safety profile, these results can truly be transformational for patients with cancer. 若 PD-1 与 VEGF 作用机制所取得的初步数据能在全球 III 期研究中得到验证，并在更多治疗场景和肿瘤类型中获得支持，同时保持可接受的安全性特征，这些成果将为癌症患者带来真正的变革性突破。 Next slide, please. We believe that 4404 is a foundational asset and a strong seamless fit with Pfizer’s oncology strategy. First, many of the cancer types where PD-1 VEGF 5 specific may have significant impact are aligned with our established disease areas of focus. These include thoracic, genitourinary and gastrointestinal cancers; second, 4404 is a multi-specific antibody. One of our 3 core modalities where we have deep experience and industry-leading capabilities; and third, there’s an opportunity to explore combinations with our industry-leading ADC portfolio, including the Vedotin class of ADCs, where a growing body of clinical data show potential synergy with anti-PD-1 agents. This strategic alignment is critical for our goal to develop 4404 into the leading PD-1 VEGF bispecific and establish it as a backlog therapy across multiple tumor types. We are laser-focused on developing 4404 with speed, with breadth and depth.  请看下一张幻灯片。我们认为 4404 是基础性资产，与辉瑞肿瘤战略高度契合。首先，PD-1/VEGF 靶点可能产生重大影响的多种癌症类型，均与我们既有的重点疾病领域相吻合，包括胸腔、泌尿生殖系统及胃肠道癌症；其次，4404 属于多靶点抗体——这是我们三大核心治疗领域之一，我们在该领域拥有深厚积淀和行业领先能力；第三，该项目可探索与我们行业领先的抗体药物偶联物（ADC）组合方案，包括维多汀类 ADC，该类 ADC 正展现出显著的临床潜力。 这正是我们拥有深厚经验和行业领先能力的三大核心治疗模式之一；第三，我们有望探索其与行业领先的抗体药物偶联物（ADC）组合疗法的协同潜力，特别是维多汀类 ADC——日益丰富的临床数据表明其与抗 PD-1 药物存在协同效应。 这种战略协同对实现 4404 成为领先的 PD-1-VEGF 双特异性抗体并确立其在多种肿瘤类型中作为后备疗法的目标至关重要。我们正以高度专注的态度推进 4404 的开发，兼顾速度、广度与深度。 Speed is facilitated by our robust global development capabilities with 7 new clinical trial initiations with 4404 expected in the near term as the first of many planned ways within our development strategy. 强大的全球研发网络为加速推进提供了有力保障，我们近期预计将开展7项 4404 项试验，这是我们开发战略中众多计划举措的首批行动。 Breath leverages our presence in multiple key disease areas where PD-1 and VEGF bispecific may have significant impact and underpins our plans to develop 4404 in multiple tumor types. Depth is driven by our unique blend of capabilities, focus and modalities to develop 4404 across multiple treatment settings, lines of therapy and novel combinations within a given disease. 深度依托于我们在多个关键疾病领域的布局——PD-1 与 VEGF 双特异性抗体在此类疾病中可能产生重大影响，并支撑着我们在多种肿瘤类型中开发 4404 的计划。这种深度源于我们独特的能力组合、聚焦方向及开发模式，能够在特定疾病领域内实现 4404 在多种治疗场景、治疗线及创新组合方案中的全面开发。 Francesca DeMartino Chief Investor Relations Officer Let’s double click on capabilities and presence. Can you elaborate on how you see those contributing to Pfizer’s development of 4404? 让我们重点探讨能力与存在感这两个方面。能否详细说明您认为它们如何推动辉瑞公司 4404 项目的发展？ Jeff Legos Certainly. We can move to the next slide, please. Pfizer has many capabilities that leave us well positioned to create value with 4404, which we view as a foundational asset. A key part of our potentially differentiated 4404 strategy is the speed in which we can move in clinical development. For oncology, speed is not just the pace of work. It’s about working smarter, leveraging our global scale and harnessing technology to enhance efficiency and innovation. We work smarter as an organization because of our team. Across our clinical and medical organizations, we have more than 50 medical oncologists who bring unparalleled experience and are empowered to make decisions and move quickly. These leaders, together with our understanding of regulatory and operations teams made Pfizer an industry leader in innovative clinical design and regulatory strategies that bring potential new therapies to patients with cancer. 当然。请翻到下一页。辉瑞拥有诸多优势，使我们能够充分利用 4404 创造价值——我们视其为基础性资产。我们差异化 4404 战略的关键要素在于临床开发的推进速度。在肿瘤领域，速度不仅关乎工作节奏，更在于更智能地运作：依托全球规模优势，运用技术手段提升效率与创新能力。 团队赋能使我们实现更智能的协作。在临床与医学部门中，我们拥有逾 50 位医学肿瘤学专家，他们凭借无可比拟的经验，被赋予决策权并能快速推进工作。这些领导者与我们对监管及运营团队的深刻理解相结合，使辉瑞在创新性临床设计和监管策略领域成为行业领军者，为癌症患者带来潜在的新疗法。 Our global scale and clinical operations and supply provide us with the agility in global clinical development. In addition to our global clinical footprint, we have 10 manufacturing and clinical trial supply sites on 3 continents, including 4 in the United States. These networks and colleagues allow us to execute our clinical development plans nimbly and with the highest quality. 我们的全球规模、临床运营及供应体系赋予我们在全球临床开发中灵活应变的能力。除覆盖全球的临床网络外，我们在三大洲设有 10 个生产及临床试验供应基地，其中 4 个位于美国。这些网络与同仁使我们能够高效执行临床开发计划，并确保最高质量标准。 Highlighting our unprecedented speed, here are a few of the many achievements, which we have made in the last 3-plus months since closing the licensing deal. First, we have submitted 5 new INDs with the FDA. We’ve worked diligently to select over 500 global clinical trial sites for our 4404 studies in more than 25 countries. And finally, we’ve accelerated time lines for tech transfer and a successfully manufactured 4404 drug product here in the United States. 为彰显我们前所未有的速度，以下是自完成许可协议签署以来三个多月内取得的部分成果。首先，我们已向美国食品药品监督管理局提交了 5 项新药临床试验申请。 我们全力推进全球临床试验站点选址工作，已在 25 个以上国家为 4404 研究项目遴选出逾 500 个试验点。最后，我们加速了技术转移进程，并在美国本土成功实现了 4404 药物的生产制造。 Francesca DeMartino Chief Investor Relations Officer Thanks, Jeff. Let’s bring some of those concepts together and talk about the near-term plans for 4404’s clinical development. Jeff Legos 谢谢，杰夫。让我们整合这些概念，讨论 4404 临床开发的近期计划。杰夫·乐高 Absolutely. Let’s move to Slide 7, please. Here, we show our first wave of planned near-term clinical trials starting with our Phase III pivotal studies. These will be the first Pfizer-sponsored studies for 4404. Already on clinicaltrials.gov, these include a study in frontline non-small cell lung cancer, including both squamous and non-squamous histologies and one in frontline metastatic colorectal cancer. Beyond these pivotal trials, we plan to initiate 5 additional studies with near-term starts. In long type cancer, these include a Phase I, Phase II study to evaluate 4404 in combination, including with some of our ADCs as well as a Phase II Phase III study in frontline extensive small cell lung cancer. In GI, we plan to initiate a Phase I, Phase II study in hepatocellular carcinoma. And in GU, we have 2 planned Phase I, Phase II studies: one, evaluating 4404 in locally advanced or metastatic urothelial carcinoma and the second one in locally advanced or metastatic renal cell carcinoma. 当然。这里展示了我们近期计划开展的首批临床试验，首先启动的是 III 期关键性研究。这些将是辉瑞公司首次为 4404 药物赞助的临床试验。目前已在 clinicaltrials.gov 网站公示，包括一项针对一线非小细胞肺癌（涵盖鳞状和非鳞状组织学类型）的研究，以及一项针对一线转移性结直肠癌的研究。 除核心试验外，我们计划启动 5 项近期启动的补充研究。在长型癌症领域，包括一项评估 4404 联合用药（含部分 ADC 药物）的 I/II 期研究，以及一项针对一线广泛期小细胞肺癌的 II/III 期研究。 在胃肠道领域，我们计划启动一项肝细胞癌的 I/II 期研究。泌尿生殖系统领域则规划两项 I/II 期研究：其一评估 4404 在局部晚期或转移性尿路上皮癌中的应用，其二则针对局部晚期或转移性肾细胞癌。 Importantly, these 7 anticipated near-term study starts are only the beginning of our plans for 4404. We’re actively working through a second wave of potential development opportunities that could deal trial starts for another 10 additional indications and 10 or more novel combinations before the end of 2026, which is a good segue to how we’re thinking about our depth of development across settings, across lines of therapies, including novel combinations. 值得注意的是，这 7 项预期近期启动的研究仅是我们针对 4404 号药物规划的开端。我们正积极推进第二波潜在开发机遇，有望在 2026 年底前启动针对另外 10 个适应症及 10 种以上新型组合方案的临床试验。这恰好引出了我们对跨场景、跨疗法（包括新型组合方案）深度开发的战略思考。 Next slide, please. We’re aiming to make 4404 a key part of our future oncology arsenal by displacing the current standard of care PD-1 and PD-L1 and VEGF agents with a new PD-1 VEGF bispecific backbone therapy across multiple tumor types. In parallel, we plan to look across lines of systemic therapy to potentially establish a new generation of chemotherapy sparing regimens by a combination of 4404 with potentially synergistic antibiotic drug conjugates. And we plan to look at opportunities to expand 4404’s reach to impact patients even earlier in their treatment journeys, such as in the neoadjuvant and adjuvant settings. 请切换到下一张幻灯片。我们致力于将 4404 打造为未来肿瘤治疗体系的核心组成部分，通过新型 PD-1-VEGF 双特异性靶向疗法取代当前标准治疗方案——PD-1/PD-L1 抑制剂及 VEGF 抑制剂，实现多瘤种适应性突破。 同时，我们计划探索全身治疗的各个阶段，通过将 4404 与具有协同潜力的ADC联合使用，建立新一代化疗方案。此外，我们还将寻求将 4404 应用于更早治疗阶段的机会，例如在新辅助治疗和辅助治疗场景中，以期更早地惠及患者。 Francesca DeMartino Chief Investor Relations Officer So Jeff, on the planned Phase III program design, how is Pfizer engaged with health authorities and how have those discussions shaped the path forward? 杰夫，关于计划中的 III 期项目设计，辉瑞公司如何与卫生部门开展合作？这些讨论如何影响了后续的推进路径？ Jeff Legos It’s an excellent question. Let’s move to Slide 10, please. We’ve been very thoughtful in our engagement with health authorities and have aligned on our global Phase III studies in non-small cell lung cancer and metastatic colorectal cancer. The goal of these discussions was to establish a framework through which we can position the 4404 development franchise to move with both maximum rigor and speed. Included in this framework are 4 core principles that we believe are consistent with the evolving health authority expectations and that may serve as a template for future 4404 pivotal trials. 这是个极好的问题。请翻到第 10 页。我们与卫生监管机构进行了深入沟通，并就非小细胞肺癌和转移性结直肠癌的全球 III 期研究达成共识。 这些讨论旨在建立一个框架，使 4404 研发项目既能以最高标准推进，又能保持高效速度。该框架包含 4 项核心原则，我们认为这些原则既符合监管机构不断演变的期望，也可作为未来 4404 关键性试验的模板。 Firstly, we’ll make overall survival at primary endpoint, either alone or a dual priority with progression-free survival. Secondly, we’ll include at least  enrollment of U.S. participants and appropriately diversify outside of that to achieve representation of our global patient population. Third, our Phase III programs will be enabled by a robust dose optimization studies in line with the U.S. FDA project Optimus. And lastly, we’ll look to engage the FDA and global health authorities for pre-Phase III advice to inform optimal trial design and execution. While these may seem straightforward, their effective and efficient implementation has the potential to meaningfully differentiate the speed and success of our clinical trials, both in the near term and beyond. 首先，我们将以总生存期作为主要终点指标，或将其与无进展生存期并列为双重优先指标。其次，我们将确保至少名美国受试者入组，并适度增加其他地区受试者比例，以实现全球患者群体的代表性。 第三，我们的 III 期项目将依托符合美国 FDA Optimus 计划的强效剂量优化研究推进。最后，我们将主动寻求 FDA 及全球卫生监管机构的 III 期前指导，以优化试验设计与执行方案。这些措施看似简单，但高效落实将显著提升临床试验的推进速度与成功率，其影响将持续至未来多年。 Francesca DeMartino Chief Investor Relations Officer Great. Let’s now transition to the 4404 clinical data starting with lung cancer. Lung cancer remains a significant unmet medical need, but not all lung cancer is the same. Can you discuss the opportunity for new therapies and the broader market segmentation. 很好。现在让我们转向 4404 的临床数据，首先从肺癌开始。肺癌仍是亟待解决的重要医疗需求，但并非所有肺癌都相同。能否请您谈谈新疗法的机遇以及更广泛的市场细分？ Jeff Legos Sure. If we can move to Slide 12, please. Let me start with some of the epidemiology. Lung cancer continues to pose a significant global health burden with over 2.7 million new diagnoses expected globally for 2025. In the United States alone, this includes approximately 315,000 incident and newly recurrent cases. Despite a decade of declining death rates, the 5year survival across stages is  for non-small cell lung cancer and only for small cell lung cancer. This underscores the urgent need for continued innovation in early detection and treatment strategies across lung cancer, a large and growing market that’s expected to be approximately billion by 2030. 好的。请翻到第 12 页。首先介绍一些流行病学数据。肺癌仍是全球重大健康负担，预计 2025 年全球新增病例将超过 270 万例。仅在美国，就包括约 31.5 万例新发及新复发病例。 尽管死亡率已连续十年下降，但各期非小细胞肺癌的 5 年生存率仍低于 ，小细胞肺癌仅为 。这凸显出肺癌领域亟需持续创新早期检测与治疗策略——该市场规模庞大且持续增长，预计到 2030 年将达到约亿美元。 On Slide 13, this shows the segmentation of lung cancer, highlighting that this tumor type is not a single disease, but rather a collection of multiple molecularly distinct diseases. This segmentation helps to stratify patients and is the foundation of precision therapy selection. The 2 primary histologic subtypes are non-small cell lung cancer, which makes up approximately 85% of the cases and small cell lung cancer accounting for the remaining 15%. 第 13 张幻灯片展示了肺癌的分型，强调这种肿瘤并非单一疾病，而是由多种分子特征各异的疾病组成的集合体。这种分型有助于对患者进行分层，也是精准治疗选择的基础。其两大主要组织学亚型为非小细胞肺癌（约占 85%病例）和小细胞肺癌（占剩余 15%）。 Non-small cell lung cancer is further divided into distinct cell types, squamous and non-squamous histology with the nonsquamous population being roughly threefold larger than squamous. Historically, the squamous-cell histology has been more difficult to effectively treat. Additionally, PD-L1 expression has become a critical biomarker for guiding immunotherapy decisions in non-small cell lung cancer. This is typically determined through what is called tumor proportion score, or TPS, which measures the fraction of cancer cells in a tumor that express PD-L1. Historically, higher TPS scores have been shown to predict better outcomes with immune checkpoint inhibitors. TPS scores greater than 1% are categorized with PD-L1 positive, accounting for approximately  of cases, and a TPS score of less than  are categorized as PD-L1 negative accounting for the remaining. 非小细胞肺癌可进一步分为不同的细胞类型，即鳞状和非鳞状组织学类型，其中非鳞状细胞群的数量约为鳞状细胞的三倍。从历史上看，鳞状细胞组织学类型的治疗效果更为困难。 此外，PD-L1 表达已成为指导非小细胞肺癌免疫治疗决策的关键生物标志物。该指标通常通过肿瘤比例评分（TPS）测定，即测量肿瘤中表达 PD-L1 的癌细胞比例。历史数据显示，TPS 评分越高，使用免疫检查点抑制剂的预后效果越好。 TPS 评分≥1%归类为 PD-L1 阳性（约占病例），而 TPS 评分 则归类为 PD-L1 阴性（占剩余病例）。 Within the non-squamous non-small cell lung cancer, there’s another tool to help define distinct molecular subtypes. This looks at the genetic drivers of cancer, bucketed into the actionable genomic alterations, including eGFR, ALK, BRAF B600 and KRAS. The presence of these mutations often prioritizes targeted small molecule therapies over immunotherapy as the first line of treatment. 在非鳞状非小细胞肺癌中，另有工具可帮助界定不同的分子亚型。该方法通过分析癌症的遗传驱动因素，将其归类为可操作的基因组改变，包括 eGFR、ALK、BRAF B600 和 KRAS 突变。这些突变的存在通常意味着应优先选择靶向小分子疗法而非免疫疗法作为一线治疗方案。 Francesca DeMartino Chief Investor Relations Officer That’s really helpful context, so data for 4404 plus chemotherapy in non-small cell lung cancer were recently presented at the Society for Immunotherapy of Cancer meeting, or SITC. Can you share the highlights of that presentation? 这确实提供了非常有价值的背景信息。关于 4404 联合化疗治疗非小细胞肺癌的数据，近期已在癌症免疫治疗学会（SITC）年会上公布。您能否分享该报告的重点内容？ Jeff Legos If we can move to Slide 14, please. Last week’s presentation at SITC was from an open-label, randomized Phase II trial of 4404 in combination with chemotherapy as the first-line treatment in advanced non-small cell lung cancer. This study is being conducted in China by 3SBio and was designed to evaluate the safety, tolerability and antitumor activity of 4404 in combination retinal therapy. 请翻到第 14 页。上周在 SITC 会议上展示的是 4404 联合化疗作为晚期非小细胞肺癌一线治疗的开放标签随机Ⅱ期试验结果。该研究由 3SBio 在中国开展，旨在评估 4404 在该适应症中的安全性、耐受性和抗肿瘤活性。 This was a head-to-head trial with the standard of caratusomizumab, an anti-PD-1 and leading approved agents in China in combination with chemotherapy. Patients of both histologies were enrolled irrespective of PDL1 TPS score. Part 1 was a chemotherapy combination with a dose escalation of 4404 in patients with non-squamous tumors versus Tislelizumab plus chemo combination arm. 这是一项与卡拉图索单抗（一种抗 PD-1 药物，中国获批的领先治疗药物）联合化疗的标准方案进行的头对头试验。无论 PD-L1 总蛋白染色评分如何，两种组织学类型的患者均被纳入研究。第一部分为非鳞状肿瘤患者采用剂量递增至 4404 单位的化疗联合方案，对照组则采用替斯利珠单抗联合化疗方案。 Part 2 was a similar design for patients with squamous disease and included both the dose escalation cohort  and a dose expansion cohort B. with 10-milligram per kilogram dose was selected for Cohort B. The efficacy data from non-squamous non-small cell lung cancer patients are shown on Slide 15 and are suggestive of deep and durable responses with a confirmed objective response rate that was numerically higher for 4404 in combination with chemotherapy across both dose levels. 第二部分针对鳞状细胞疾病患者采用了类似设计，包含剂量递增队列 A 和剂量扩展队列 B。最终选定 10 毫克/千克剂量用于队列 B。 非鳞状非小细胞肺癌患者的疗效数据见第 15 页幻灯片，显示出深层且持久的反应，经确认的客观缓解率在两个剂量水平下均高于 4404 联合化疗组。 As shown in the left panel, the confirmed objective response rate for 4404 plus chemotherapy was 50% at the 5-milligram per kilogram dose and approaching 60% for the 10 mg per kilogram dose compared to  for the Tislelizumab combination therapy. The depth and durability of response for patients receiving 4404 at the 10-milligram per kilogram dose is shown on the spider plot on the right. 如左侧面板所示，4404 联合化疗在 5 毫克/千克剂量下的确认客观缓解率为 50%，10 毫克/千克剂量下接近 60%，而替斯利珠单抗联合疗法的该指标 。 右侧蜘蛛图展示了接受 4404（10 毫克/千克剂量）治疗患者的反应深度与持久性。 Each line represents an individual patient and shows tumor shrinkage from baseline with the lines going down are good. In addition, you can see that many of the lines continue to further deepen and stay there, reflecting a deepening of this response over time and providing an early glimpse of the response durability. We’re particularly encouraged by the efficacy for the 10milligram per kilogram dose group, which has informed the planned Phase III pivotal start and will also be the focus of today’s discussion around these Phase II results. 每条曲线代表一名患者，显示肿瘤相对于基线的缩小程度，曲线向下延伸代表疗效良好。此外，您可以看到许多曲线持续下移并保持稳定，这反映出疗效随时间推移不断深化，并初步揭示了疗效的持久性。 10 毫克/千克剂量组的疗效尤为令人鼓舞，该结果不仅为计划中的 III 期关键试验启动提供了依据，也将成为今日围绕 II 期试验结果讨论的核心焦点。 On Slide 16 are the efficacy data in the squamous histology group. Let’s start with Cohort  in the top panel. The results for patients receiving 4404 at the 10-milligram per kilogram dose are suggestive of durable responses independent of PD-L1 expression. The depth of response is shown in the waterfall plot in the left panel. These plots represent tumor shrinkage from baseline with longer downward bars reflecting a larger decrease in tumor size. These data corresponds to a confirmed overall response rate of 75%. 第 16 张幻灯片展示了鳞状组织学组的疗效数据。首先看顶部面板中的  队列。接受 4404 药物 10 毫克/千克剂量的患者结果表明，无论 PD-L1 表达水平如何，均可获得持久的疗效。 左侧瀑布图展示了反应深度。这些图表反映了肿瘤相对于基线的缩小程度，向下延伸的柱状越长，表示肿瘤体积缩减幅度越大。该数据对应的总体确认反应率为 75%。 The spider plot on the right shows tumor shrinkage over time. Again, we see most of the lines going down and tending to stay down over the period of evaluation. This provides an early glimpse of the durability of responses even in patients having the harder to treat squamous cell histology. And if we look at the panel on the bottom of the slide, these are data from the dose expansion cohort B, which started subsequent to Cohort A and therefore, has considerably shorter duration of follow-up at the time of the data cutoff. 右侧的蜘蛛图显示了随时间推移的肿瘤缩小情况。 我们再次看到多数曲线呈下降趋势，并在评估期间持续保持低位。这为疗效的持久性提供了早期观察依据——即便在鳞状细胞组织学这类更难治疗的患者群体中亦然。若观察幻灯片底部的数据面板，这些来自剂量扩展队列 B 的结果，该队列在队列 A 之后启动，因此在数据截止时点的随访时间明显较短。 Nonetheless, even with very limited duration of follow-up, we continue to see encouraging early response rates in patients receiving 4404. Next slide, please. The observed safety profile shown here on Slide 17, which generally consistent with the known safety profiles of chemotherapy combined with PD-L1 and angiogenesis inhibitors. The most common treatmentrelated adverse events are listed on the left-hand side of the slide in order of decreasing frequency in patients receiving 4404. The aggregate frequencies are shown on the right in purple for 4404 plus chemo groups and in gray, for Tislelizumab plus chemo groups. The hematologic adverse events were the most common type for both arms, consistent with a chemotherapy regimen. In total, Grade 3 and higher treatment-related adverse events were observed in 39% of patients receiving 4404 of a 10-milligram per kilogram dose level versus approximately 33% in patients receiving Tislelizumab combination therapy. 尽管随访时间非常有限，我们仍持续观察到接受 4404 治疗的患者呈现令人鼓舞的早期反应率。请看下一张幻灯片。 第 17 页展示的安全性特征总体符合化疗联合 PD-L1 抑制剂及抗血管生成抑制剂的已知安全性特征。幻灯片左侧按发生频率降序列出了 4404 治疗组最常见的治疗相关不良事件。右侧紫色区域显示 4404 联合化疗组的总发生率，灰色区域显示替西利珠单抗联合化疗组的总发生率。 两组最常见的不良事件均为血液学不良事件，符合化疗方案特征。在 4404 组（剂量 10 毫克/千克）中，3 级及以上治疗相关不良事件发生率为 39%，而替西利珠单抗联合治疗组发生率约为 33%。 These grade 5 treatment-related adverse events occurred in patients receiving 4404 at a 10-milligram per dose level and in 1 patient receiving Tislelizumab combination. Importantly, treatment-related adverse events leading to drug discontinuation were low. Overall, the Phase II data are supportive of the promising efficacy and manageable safety profile from 4404 in combination with chemotherapy for patients with advanced non-small cell lung cancer independent of tumor histology and independent of PD-L1 expression. These results build upon the encouraging monotherapy for 4404 presented at ASCO earlier this year. and strengthen our confidence in the selective dose for the planned Phase III pivotal trial. 这些 5 级治疗相关不良事件发生于接受 4404 单药治疗（剂量为 10 毫克）的患者中，以及 1 例接受替斯利珠单抗联合治疗的患者中。值得注意的是，导致停药的治疗相关不良事件发生率较低。 总体而言，II 期临床数据证实：对于晚期非小细胞肺癌患者，无论肿瘤组织学类型或 PD-L1 表达水平如何，4404 联合化疗均展现出令人鼓舞的疗效及可控的安全性特征。这些结果进一步巩固了今年 ASCO 会议上公布的 4404 单药治疗的积极数据，并增强了我们对计划开展的 III 期关键试验中选定剂量的信心。 Francesca DeMartino Chief Investor Relations Officer And based on the data you just recapped, what’s next for 4404 in lung cancer? Jeff Legos Supported by this very encouraging Phase II data, we’ve worked with health authorities to design a single global Phase III study plus chemotherapy in both squamous and non-squamous cell lung cancer. The design of this trial is shown here on Slide 18. It will enroll patients with locally advanced or metastatic disease who have no known actionable genomic alterations and who have not received prior systemic therapy for advanced or metastatic disease. Both PD-L1 positive and PD-L1 negative patients will be eligible. Patients will be divided into 2 cohorts based on histology and randomized to receive chemotherapy 基于这项令人鼓舞的 II 期研究数据，我们与卫生部门合作设计了一项全球性 III 期研究，针对鳞状细胞和非鳞状细胞肺癌患者，同时采用化疗方案。 该试验设计详见第 18 页幻灯片。入组对象为局部晚期或转移性疾病患者，需满足：无已知可操作基因组改变，且未接受过晚期或转移性疾病的全身治疗。PD-L1 阳性与阴性患者均符合入组条件。患者将根据组织学特征分为两组，并随机接受化疗。 in combination with either 4404 or pembrolizumab. After the initial number of treatment cycles, pages will continue with maintenance therapy. The study is designed to enroll about 700 participants in the squamous cell histology cohort and about 800 participants in the non-squamous cohorts. The dual primary endpoints of the study are progression-free survival and overall survival. 联合 4404 或派姆单抗使用。完成初始治疗周期后，患者将继续接受维持治疗。该研究计划招募约 700 名鳞状细胞组织学亚组受试者及约 800 名非鳞状细胞亚组受试者。研究的双主要终点为无进展生存期和总生存期。 If successful, we believe this study could support potential approvals in the first-line setting for both squamous and nonsquamous histology, non-small cell lung cancer. As I reviewed earlier, our plans with 4404 also extend in the extensive stage small cell lung cancer. 若研究成功，我们相信这将为鳞状和非鳞状组织学类型非小细胞肺癌的一线治疗方案提供潜在的获批依据。正如我先前所述，我们对 4404 的规划还延伸至广泛期小细胞肺癌领域。 If we flip now to Slide 19, we’ll see the design of our planned Phase II/III trial in this indication. This study will begin with a Phase II open-label cohort, evaluating 4404 in combination with chemotherapy. If the data from the Phase II part of the study are supported, we’ll then rapidly and seamlessly move into a Phase III double-blind randomized portion. Here, we will evaluate the combination of chemotherapy with either 4404 at the Phase III dose where the anti-PD-L1 monoclonal antibody, Tislelizumab. The primary endpoint of this trial will be overall survival. 现在请翻到第 19 页，我们将看到针对该适应症的计划中的 II/III 期试验设计。该研究将首先开展 II 期开放标签队列，评估 4404 联合化疗的疗效。若 II 期部分数据支持，我们将迅速无缝过渡至 III 期双盲随机阶段。 在此阶段，我们将评估化疗联合 4404（采用 III 期剂量）与抗 PD-L1 单克隆抗体替西利珠单抗（Tislelizumab）的联合疗效。本试验的主要终点为总生存期。 If successful, we believe this study could support potential approval for 4404 in first-line extensive-stage small cell lung cancer. And together with our non-small cell lung cancer study, support our broader ambition to displace traditional checkpoint inhibitors in the lung cancer treatment paradigm. 若研究成功，我们相信这将为 4404 在广泛期小细胞肺癌一线治疗中的潜在获批提供支持。结合我们针对非小细胞肺癌的研究成果，这将助力我们实现更宏伟的目标——在肺癌治疗模式中取代传统检查点抑制剂。 Francesca DeMartino Chief Investor Relations Officer Thanks, Jeff. To conclude, could you provide an overview of how your plans for 4404 fit within the broader lung cancer portfolio? 谢谢，杰夫。最后，能否请您概述一下您对 4404 的规划如何融入更广泛的肺癌产品组合？ Jeff Legos Absolutely. If we could just move to Slide 20, please. So here, we could see a summary of our fluid medicines under late-stage lung cancer agents currently in development. Starting at the top, we have our approved targeted small molecule medicines. These include our BRAFTOVI and MEKTOVI combination, which is approved to treat BRAF V600E metastatic non-small cell lung cancer and Lorena, which is approved for ALK-positive metastatic non-small cell lung cancer. Beyond our targeted small molecules, we are also developing 4404 as well as the antibody drug conjugates, SP and PD-L1b. Shown in the darker blue are the ongoing Phase III trials for SP and PD-L1b in non-small cell lung cancer. 好的。请翻到第 20 页。在此页面上，我们可以看到目前处于后期研发阶段的晚期肺癌治疗药物——流体药物的概述。 从顶部开始，我们拥有已获批的靶向小分子药物。其中包括获批用于治疗 BRAF V600E 突变转移性非小细胞肺癌的 BRAFTOVI 与 MEKTOVI 联合疗法，以及获批用于 ALK 阳性转移性非小细胞肺癌的 Lorena。 除靶向小分子药物外，我们还正在开发 4404 以及抗体偶联药物 SV 和 PD-L1V。深蓝色部分展示的是抗体偶联药物 SV 和 PD-L1V在非小细胞肺癌领域正在进行的 III 期临床试验。 The second line study of SP in nonsquamous disease with any PD-L1 status is anticipated to read out next year. In addition, we’ve recently initiated both a frontline study of SV in patients with TPS high disease and histology agnostic second line and later study with PD-L1B. There are also future opportunities for SP in the first-line setting in patients with PD-L1 low or PDL1 negative tumors. 针对非鳞状癌患者（无论 PD-L1 状态）开展的 SP 二线研究预计将于明年公布结果。此外，我们近期启动了两项研究：一项针对 TPS 高表达患者开展的 SV 一线研究，以及一项不考虑组织学特征的 PD-L1V 二线及后续研究。未来在 PD-L1 低表达或阴性肿瘤患者中，SV 在一线治疗领域也存在应用潜力。 We’ve just detailed our Phase III frontline studies for 4404 in both small cell and non-small cell lung cancer. However, we can also see the potential for 4404 in earlier settings of non-small cell lung cancer treatment. And of course, there’s the Phase I, Phase II study that I mentioned earlier, where we plan to begin exploring 4404 in multiple combinations, including those with our antibody drug conjugates, where we have a growing body of data suggestive of potential synergy when combined with anti-PD-1 therapy. 我们刚刚详细介绍了 4404 在小细胞肺癌和非小细胞肺癌中的 III 期一线研究。但我们也看到了 4404 在非小细胞肺癌早期治疗中的潜力。 当然，还有我之前提到的 I 期、II 期研究，我们计划开始探索 4404 的多重联合用药方案，包括与我们抗体药物偶联物的组合——现有数据表明，该药物与抗 PD-1 疗法联合使用时可能产生协同效应。 Francesca DeMartino Chief Investor Relations Officer Thank you for that great recap of our lung cancer strategy, Jeff. Shifting gears, can we now speak about the colorectal cancer for which Pfizer is also pursuing a near-term Phase III start for 4404 ? 杰夫，感谢你对肺癌战略的精彩总结。现在换个话题，我们能否讨论一下辉瑞公司同样计划近期启动 4404 药物 III 期临床试验的结直肠癌项目？ Jeff Legos If we could advance to Slide 22, please. Like lung cancer, colorectal cancer represents a significant unmet need and a substantial opportunity for new therapies. It’s one of the most commonly diagnosed cancers globally with more than 1.5 million new diagnoses expected in 2025 alone. It’s the second most frequent cause of cancer-related death in the United States. And despite recent advances, it continues to remain difficult to treat. This is particularly true in the metastatic setting, where the 5-year survival in the United States is a dismal – through our development of 4404, we hope to improve outcomes for patients with colorectal cancer and expand our leadership in a large and growing marketplace that has a projected 2030 size of around $9 billion. 请切换至第 22 页幻灯片。与肺癌类似，结直肠癌同样存在显著的未满足医疗需求，为新疗法提供了巨大机遇。作为全球最常见的癌症之一，仅 2025 年预计新增病例就将超过 150 万例。在美国，它是导致癌症相关死亡的第二大病因。 尽管近期治疗手段有所进步，该病仍难以治愈。转移性结直肠癌尤为棘手，美国患者五年生存率极低——通过开发 4404 项目，我们期望改善结直肠癌患者预后，并扩大公司在这一庞大且持续增长的市场中的领导地位。该市场预计到 2030 年规模将达到约 90 亿美元。 Francesca DeMartino Chief Investor Relations Officer Great. And then next, could you speak briefly about how metastatic colorectal cancer is classified and treated and the areas of the market where Pfizer is aiming to make an impact. 很好。接下来，能否请您简要说明转移性结直肠癌的分类与治疗方式，以及辉瑞公司计划在哪些市场领域产生影响？ Jeff Legos Sure. If we could just move to Slide 23. Here, you can see that treatment of metastatic colorectal cancer or metastatic CRC for short, is guided by various tumor characteristics in genetic markers, considering unresectable or metastatic CRC, firstline treated typically involve systemic therapy with regimens that include chemotherapy, biologics, targeted therapies and/or immune checkpoint inhibitors. Therapeutic regimens are driven by the molecular profile of the tumor being treated, one way in which metastatic CRCs are classified as by microsatellite stability, or MSI high status. MSI high patients typically have deficient DNA, mismatch repair systems and represent approximately 5% of metastatic CRC. These patients are often treated with immune checkpoint inhibitors as MSI status is a key biomarker to help predict response to these therapies. The remaining of patients are classified as microsatellite stable and are typically treated with anti-EGFR or anti-VEGF therapy. These patients will be the focus of our planned 4404 Phase III studies in metastatic CRC. And as we will test dual anti-VEGF anti-PD-1 regimen including an anti-VEGF monoclonal antibody. Metastatic CRC tumors are also classified by genetic mutations or amplifications focusing on where Pfizer medicines are having an impact. There are 60 mutations, which affect about to of patients with metastatic CRC. And there are also HER2-positive metastatic CRC, which represents about to of CRC patients. With 4404, we aim to improve patient outcomes by building a diverse franchise that can attack tumors from multiple angles. 好的。请翻到第 23 页。这里可以看到，转移性结直肠癌（简称转移性 CRC）的治疗方案需根据肿瘤的遗传标记特征进行指导。对于不可切除或转移性 CRC，一线治疗通常采用全身治疗方案，包括化疗、生物制剂、靶向治疗和/或免疫检查点抑制剂。 治疗方案取决于待治疗肿瘤的分子特征。转移性 CRC 的分类标准之一是微卫星不稳定性（MSI 高状态）。MSI 高状态患者通常存在 DNA 错配修复系统缺陷，约占转移性 CRC 患者的 5%。由于 MSI 状态是预测此类疗法反应的关键生物标志物，这类患者常接受免疫检查点抑制剂治疗。 其余患者归类为微卫星稳定型，通常采用抗 EGFR 或抗 VEGF 疗法。这些患者将成为我们计划开展的 4404 期 III 期转移性结直肠癌研究重点。该研究将测试包含抗 VEGF 单克隆抗体的双重抗 VEGF-抗 PD-1 方案。 转移性结直肠癌肿瘤还根据基因突变或扩增进行分类，重点关注辉瑞药物发挥作用的靶点。通过 4404 项目，我们旨在构建多元化产品线，从多角度攻击肿瘤，从而改善患者预后。 Francesca DeMartino Chief Investor Relations Officer Okay. Great. Thanks for that, Jeff. Can you next speak a bit about the data that supports your plans for 4404 in metastatic colorectal cancer. 好的。太好了。谢谢你，杰夫。接下来能否请你谈谈支持你们在转移性结直肠癌领域推进 4404 计划的相关数据？ Jeff Legos Sure. If we turn to Slide 24. Here, we could see some of the data which were presented at the recent European Society of Medical Oncology Meeting last month. These data come from a Phase II trial in China conducted by 32Bio evaluating 4404 in combination with chemotherapy in patients with treatment-naive metastatic CRC. Patients with an MSI high status were excluded from this study. The results are shown from a cohort of patients receiving 10 milligrams per kilogram of 4404 every other week in combination with a modified FOLFOX chemotherapy regimen, which is the regimen we plan to take forward into Phase III. 好的。请翻到第 24 页。这里展示了上月欧洲医学肿瘤学会会议上公布的部分数据。这些数据源自 32Bio 在中国开展的 II 期临床试验，评估了 4404 联合化疗治疗初治转移性结直肠癌患者的疗效。本研究排除了高微卫星不稳定性（MSI-H）状态的患者。 结果展示的是接受每两周一次 4404（剂量 10 毫克/千克）联合改良 FOLFOX 化疗方案的患者队列数据，该方案正是我们计划推进至 III 期的治疗方案。 We observed encouraging antitumor activity in this study with a greater than 57% confirmed objective response rate and greater than 95% disease control rate achieved with our planned Phase III regimen. On the left, you can see the depth of the responses with longer downward bars reflecting larger decreases in tumor size. And in the spider plot on the right, you can see the data capturing durability with many responses ongoing at the time of the data cutoff. 在本研究中，我们观察到令人鼓舞的抗肿瘤活性：采用预定的 III 期治疗方案，确认客观缓解率超过 57%，疾病控制率超过 95%。左侧图表显示了疗效深度，向下延伸的柱状图越长，表明肿瘤体积缩减幅度越大。右侧蜘蛛图则呈现了疗效持久性数据，在数据截止时点仍有大量患者持续保持缓解状态。 As we move to Slide 25. Here, you can see data highlighting the manageable safety profile of 4404 plus chemotherapy in the Phase II study. In the interest of time, I’ll highlight that with our planned Phase III regimen, we saw ......grade 3 or higher immune-related adverse events and no treatment-related adverse events leading to 4404 discontinuation or death. Looking across all dose regimens in this study, the proportion of patients with grade 3 or higher immune-related adverse events and treatment-related AEs leading to 4404 discontinuation or death were very low at and , respectively. Together with the encouraging anticancer activity observed in this study, these results support our plans to evaluate 4404 plus modifying full fox in the Phase III trial. 请翻至第 25 页。此处数据突显了 4404 联合化疗在 II 期研究中可控的安全性特征。为节省时间，我重点说明：在计划的 III 期治疗方案中，我们观察到不分3 级及以上免疫相关不良事件，但未出现导致 4404 停药或死亡的治疗相关不良事件。 纵观本研究所有剂量方案，出现 3 级及以上免疫相关不良事件的患者比例极低，因治疗相关不良事件导致 4404 停药或死亡的比例同样极低。结合本研究中观察到的令人鼓舞的抗癌活性，这些结果支持我们在 III 期试验中评估 4404 联合修饰型全 FOX 方案的计划。 Francesca DeMartino Chief Investor Relations Officer Could you please expand a bit on the design of the planned Phase III study? Jeff Legos First, if we could just advance to Slide 26, please. Here, we can see an overview of our planned study in first-line metastatic colorectal cancer. The study, which is currently posted on clinicaltrials.gov is a global double-blind Phase III trial, evaluating 4404 against the anti-VEGF monoclonal antibody biz both in combination with modified Wallbox. Similar to the Phase II study, this trial will exclude patients who are MSI-high focusing on the population of patients where PD-1, PD-L1 checkpoint inhibitors have historically shown limited benefit. This study is designed to enroll about 800 participants and has dual primary endpoints are progression-free and overall survival. If successful, we believe this study could support a potential approval in first-line metastatic CRC as well as our broader inhibition to displace traditional anti-VEGF therapy in the metastatic CRC treatment paradigm. 首先，请切换至第 26 页幻灯片。此处展示了我们针对一线转移性结直肠癌研究计划的概述。 该研究目前已在 clinicaltrials.gov 网站公示，是一项全球性双盲 III 期试验，旨在评估 4404 与抗 VEGF 单克隆抗体 biz 联用改良型 Wallbox 方案的疗效。与 II 期研究类似，本试验将排除高微卫星不稳定性(MSI-H)患者，重点针对 PD-1/PD-L1 检查点抑制剂疗效有限的患者群体。 本研究计划招募约 800 名受试者，设无进展生存期与总生存期双重主要终点。若取得成功，我们相信该研究不仅能支持 PD-1 抑制剂在转移性结直肠癌一线治疗领域的潜在获批，更有望推动其在转移性结直肠癌治疗模式中逐步替代传统抗 VEGF 疗法。 Francesca DeMartino Chief Investor Relations Officer Thanks, Jeff. This has been a very informative discussion. So to summarize our conversation today, I would say Pfizer Oncology is aggressively moving forward with an ambitious development plan to unlock value for our foundational asset 谢谢，杰夫。这次讨论非常富有启发性。综上所述，辉瑞肿瘤业务正积极推进一项雄心勃勃的研发计划，旨在为我们的核心资产释放价值。 4404 aiming to generate data that could pending clinical and regulatory success to make it a backbone treatment across multiple cancer types. At a high level, several parts of today’s conversations stand out. First, 4404 is a seamless fit with Pfizer’s oncology strategy, leveraging our deep expertise in both the development of multispecific antibodies and in relevant disease areas and the global development plan builds on a truly global R&D presence. 4404 旨在生成关键数据，待临床及监管成功后，有望成为多种癌症类型的核心治疗方案。从宏观层面看，今日讨论的若干要点尤为突出：首先，4404 与辉瑞肿瘤战略完美契合，既依托我们在多特异性抗体研发及相关疾病领域的深厚积淀，又依托全球研发网络构建了真正的全球化开发计划。 Second, a three-pronged strategy is in place to execute the development plan. Speed is exemplified by 7 planned near-term clinical trial starts, including 2 Phase III studies in the first of many planned ways. Breadth is demonstrated by the multiple tumor types in these planned near-term trial starts and DUC encompasses multiple treatment settings, lines of therapy and the evaluation of novel combinations with our leading ADC portfolio within a given disease area. Third, we continue to be rigorous in our approach to 4404’s development, utilizing encouraging clinical results to make data-driven decisions and create an enabling framework for interactions with health authorities so that 4404 program may progress with both maximum rigor and speed. And finally, the tumor types encompassed by the 4404 development plan are not only grounded in Pfizer’s current commercial presence but also represent attractive opportunities in disease areas with a large unmet medical need. We’ll now begin the Q&A session with Jeff, Johanna and Arati. And as a reminder, our Pfizer Flash series is designed as an educational deep dive into our pipeline programs. I’ll, therefore, kindly ask participants to keep questions focused on 4404 and the data and development plans discussed today and avoid questions that would require us to provide forward-looking financial projections. While we’re happy to clarify any information we shared during the presentation, we will not be offering estimates beyond what has already been communicated. 其次，我们已制定三管齐下的战略来执行开发计划。在速度方面，计划近期启动 7 项临床试验，其中包括两项 III 期研究，这只是众多计划举措中的第一步。在广度方面，这些近期启动的试验涵盖多种肿瘤类型，而 DUC 项目则涉及多种治疗场景、治疗线，并在特定疾病领域内评估我们领先的抗体药物偶联物（ADC）产品组合的新型联合疗法。 第三，我们持续以严谨态度推进 4404 的研发进程，依托积极的临床结果进行数据驱动决策，并构建与监管机构高效协作的框架，确保该项目在最大程度的严谨性与速度间取得平衡。 最后，4404 研发计划涵盖的肿瘤类型不仅立足于辉瑞当前的商业布局，更在存在巨大未满足医疗需求的疾病领域展现出诱人机遇。。现由 Jeff、Johanna 和 Arati 主持问答环节。请注意，辉瑞快讯系列旨在深入解析我们的研发管线项目。 因此恳请各位提问聚焦于 4404 项目及今日讨论的数据与开发计划，避免涉及需要我们提供前瞻性财务预测的问题。我们乐意澄清本次会议中披露的任何信息，但不会提供超出已公布内容的预测数据。 Thank you for your understanding. With that, we’re ready to take the first question. Operator, if you could please assemble the queue, and Jeff, I’ll turn it over to you to lead us through it. 感谢您的理解。现在，我们准备好回答第一个问题。主持人，请您组织提问队列，杰夫，接下来请您主持提问环节。 This is Nishant on for Jeff. So my question is on the glass overall. The PD-1 REG class is kind of becoming crowded in lung cancer. So beyond hitting the primary end points, are there any specific features on the final – like a label like superior safety or efficacy in [indiscernible] or even those inconvenience that you believe will be essential for achieving like dominant market share. 我是尼尚特，代替杰夫提问。我的问题是关于整体市场格局。PD-1 调节剂在肺癌领域正变得日益拥挤。那么在达到主要终点之外，您认为在最终标签中是否需要突出某些特定特征——比如更优的安全性或疗效，甚至那些您认为对实现主导市场份额至关重要的不便之处？ Jeff Legos Thanks, Nishant. And maybe I’ll start and then turn it over to Johanna. So as mentioned, right, the trials are designed for superiority with what we believe to be a very clinically meaningful improvement in both progression-free survival and overall survival or overall survival alone based on the exact design of the trial. I think with respect to how we intend to differentiate here, I think we showed a few examples of combinations with standard of care. And then ultimately, kind of the next wave of innovation, we’ll move into novel combinations. 谢谢，尼尚特。我先开始说明，然后交给约翰娜。正如之前提到的，这些试验旨在验证疗效优越性，我们相信无论是在无进展生存期和总生存期，还是仅在总生存期方面，都能实现具有重要临床意义的改善——具体取决于试验的精确设计。 关于差异化策略，我们展示了若干与标准治疗方案的联合用药案例。而创新浪潮的下一阶段，我们将推进新型联合治疗方案的研发。 So we believe through a very rapid and clinically meaningful improvements in our endpoints. We believe that will help us to different as well as to novel combinations. But Johanna, I’ll turn it over to you to share a little bit more, Nishant, how you’re thinking about how to enhance the label and success. 因此我们相信，通过在终点指标上实现快速且具有临床意义的改善，这将有助于我们开发出差异化且创新的组合方案。不过乔安娜，现在请你来分享更多细节——尼尚特，你对如何优化适应症范围和提升疗效有何见解？ Johanna Bendell Chief Development Officer of Oncology Thank you so much, Jeff, and thank you so much for the question. I think, first of all, when we think about how we ideally combined with our Pfizer portfolio and the next wave of innovation that Jeff was mentioning. We are really excited in particular about looking at combinations with our antibody drug conjugates. We’re thinking about not only non-small cell lung cancer, but potentially other areas where Pfizer non-ADCs are sitting in terms of the standard of care. 非常感谢你，杰夫，也非常感谢你的提问。首先，当我们思考如何理想地将辉瑞产品组合与杰夫提到的下一波创新相结合时，我们尤其对与抗体药物偶联物（ADC）的联合应用感到兴奋。我们不仅关注非小细胞肺癌领域，还考虑在辉瑞非 ADC 药物作为标准治疗方案的其他领域进行探索。 I think also in terms of subgroups that we would be thinking about for certain our trials will be planned for subgroups that we are considering to be able to preplan these and bake them into the clinical trial design. So as you see the clinical trials coming forward, and if you want to understand a bit better the subgroups that we’re looking at, you’ll see those within not only the Phase IIIs, but also within the exploratory trials that were we’re doing, so you can see different populations that we’re looking for. 我认为在亚组研究方面，我们必然会针对特定亚组规划试验方案，将这些预先设定的方案融入临床试验设计中。 因此，当您看到临床试验推进时，若想更深入理解我们关注的亚组，不仅能在 III 期试验中看到相关设计，在我们开展的探索性试验中也能发现这些亚组设置，从而了解我们针对的不同人群群体。 We’re always excited to try to think about bringing treatment earlier in the cancer setting to have even more efficacy for our patients. When we think about safety, we’ve seen a differential where 2 antibodies, if we give a PD-1 inhibitor and a VEGF inhibitor separately, we may have issues in terms of being able to maximize the efficacy for patients on safety differentials that we see by giving 2 separate antibodies. And 1 thing that we’re very excited about with the combination of bispecific is that we’re happy – we’re excited to localize the treatment effect more to the tumors to potentially decrease the safety issues that we could potentially see by treating with both PD-1 and a VEGF antibody alone. And then we’re also very interested in tying into our trials, the patient-related outcomes to make sure that we’re really seeing benefits for our patients not only in terms of overall efficacy that we see within the clinical trials but also in how they’re feeling. 我们始终致力于探索在癌症治疗中更早介入治疗方案，以期为患者带来更显著的疗效。在安全性考量方面，我们观察到两种抗体存在差异：若单独使用 PD-1 抑制剂和 VEGF 抑制剂，可能因安全性差异导致无法最大化患者疗效。 而双特异性抗体联合治疗令我们倍感振奋之处在于：它能将治疗效果更精准地定位于肿瘤部位，从而有望降低单独使用 PD-1 和 VEGF 抗体治疗时可能出现的副作用风险。 此外，我们非常重视将患者相关结局指标纳入临床试验，以确保患者不仅在试验整体疗效层面获益，更能切实感受到治疗带来的改善。 Steve Scala TD Cowen I have a few questions. Do you think Phase III results in lung cancer will set the upper bound for efficacy for PD-1 VEGF, the whole class across tumors. And what overall survival hazard ratio do you need to see in lung cancer to be convinced that this class has transformative potential across tumors? So that’s the first question. 我有几个问题。您认为肺癌的 III 期试验结果是否会为 PD-1/VEGF 抑制剂在所有肿瘤类型中的疗效设定上限？在肺癌领域需要观察到怎样的总生存期风险比，才能确信该类药物具有跨肿瘤类型的变革潜力？这是第一个问题。 Second question is, is it possible that big centers will have competitive PD-1 VEGF trials ongoing. Some theorize the reason KEYTRUDA had such a successful clinical trial program is that they got the best patients at each center. If you believe that is true, then how can Pfizer enjoy that same advantage. 第二个问题是，大型中心是否可能同时开展具有竞争力的 PD-1 和 VEGF 临床试验？有观点认为，KEYTRUDA 临床试验项目之所以如此成功，是因为他们在每个中心都获得了最优质的患者。如果这种观点成立，那么辉瑞如何才能获得同样的优势？ Jeff Legos Thanks for the question, Steve. And I try to capture them if we miss any, just remind me. So I think your first question with respect to will the Phase III results in lung cancer set the overall benchmark. So across multiple cancers. So I think we recognize that lung cancer has been one of the more immunogenic cancers where patients have responded to anti-PD-1. 谢谢你的提问，史蒂夫。如果遗漏了任何问题，我会尽力补充，请随时提醒我。关于你的第一个问题：肺癌的 III 期试验结果是否会成为整体基准——即适用于多种癌症的情况。我们认识到肺癌是免疫原性较强的癌症之一，患者对抗 PD-1 治疗有良好反应。 So we believe this is an important first place to study the medicine and it’s the area where we have the largest proportion of Phase II data but we also recognize that every cancer is different and every combination is different, which is why we have a very broad and deep development plan because we don’t expect to just extrapolate the results from 1 cancer to another. And as you’re well aware, colorectal cancer and non-small cell lung cancer are very different with respect to how patients respond to anti-PD-1 or PD-L1 therapies. 因此我们认为这是研究该药物的首要重要领域，也是我们拥有最多 II 期数据的领域。但我们也认识到每种癌症都各不相同，每种联合用药方案也各不相同，这正是我们制定了广泛而深入的研发计划的原因——我们不期望简单地将一种癌症的试验结果外推到另一种癌症。 正如您所知，结直肠癌与非小细胞肺癌在患者对抗 PD-1 或 PD-L1 疗法的反应方面存在显著差异。 In terms of the clinically meaningful benchmarks, I would just reiterate the point that I made previously. And that here, we are designing our studies based on the sample sizes that were shown to exhibit both a clinically meaningful and statistically significant benefit for for patients with respect to our time-to-event endpoint. 就临床意义基准而言，我只想重申先前提出的观点：我们当前的研究设计是基于样本量，该样本量已被证实能为患者在事件发生时间终点方面带来兼具临床意义和统计学显著性的获益。 I think your last question was around sort of clinical trial sites and potentially getting the best patients. I think the best patients aren’t necessarily representative of real-world patients. But that being said, I think this is where the breadth and the depth of our expertise across a wide range of cancers including non-small cell lung cancer and colorectal cancer will already help us in terms of having this established clinical trial footprint and deep relationships with these investigators. 我认为您最后的问题涉及临床试验站点以及如何筛选最理想的患者。我认为最理想的患者未必能代表真实世界的患者群体。但话虽如此，我认为这正是我们优势所在——我们在包括非小细胞肺癌和结直肠癌在内的多种癌症领域拥有广度与深度兼备的专业知识，这将助力我们依托已建立的临床试验网络，并与这些研究者建立深厚的合作关系。 And we have already identified more than 500 clinical centers who we have worked with across all of our previous studies who have confirmed their willingness to participate in these upcoming Phase III clinical trials. So we will believe – we believe that we will be able to sort of reach and target patients that are truly representative of those which we are seeking an indication in, including both the United States, Europe and Asia. 我们已确定超过 500 家临床中心，这些机构曾参与我们所有前期研究，并确认愿意加入即将开展的 III 期临床试验。因此我们相信——确信我们能够覆盖并锁定真正符合适应症要求的患者群体，涵盖美国、欧洲及亚洲地区。 Evan Seigerman BMO Capital Markets Equity Research We saw some data for the competitive Summit asset. Maybe some context that data and how you think your asset will be able to compete and really show that this is the PD-L1 VEGF bispecifics? 我们看到竞争对手 Summit 资产的相关数据。能否说明这些数据的背景，以及贵公司资产如何实现差异化竞争，真正展现其作为 PD-L1 VEGF 双特异性抗体的优势？ And secondarily, when you were evaluating potential assets to in-license, what were some of the unique features of this antibody that drove you to the deal? 其次，在评估潜在资产进行引进许可时，这款抗体有哪些独特特性促使您达成这笔交易？ Jeff Legos And maybe I’ll ask Arati Rao, who’s our 4404 franchise lead for this molecule to comment a bit on maybe some of the preclinical data and then what specifically excited her [indiscernible] diligence and then currently with respect to the clinical portfolio. We’re now, I think, more than 650 patients have already been treated with 4404 . So Arati, over to you. 或许我会请我们的 4404 项目负责人阿拉蒂·拉奥谈谈部分临床前数据，以及哪些具体方面让她感到振奋——特别是关于尽职调查和当前临床项目组合的情况。目前已有超过 650 名患者接受了 4404 治疗。阿拉蒂，请您分享。 Thank you, Jeff. Thanks, Evan, for the question. So in terms of the preclinical data, I will tell you that the unique tetravalent structure or a tetra body that 707 or 4404 is what attracted me when I first began looking at this package, the tetravalent structure allows for each arm to simultaneously bind PD-1 and VEGF together. In the presence of VEGF, 707 forms multiplers and this multimerization or daisy chaining as we call it, is what allows for increased affinity for PD-1. And then that leads to increased binding of PD-1 by almost 10x. The fully functional VEGF arm on this molecule is really interesting, and it actually [indiscernible] it drive angiogenesis, anti-angiogenesis, it also creates an immunosuppressive environment that we see in the TME. All of these preclinical data will be kind of attracted us towards it. The VEGF inhibition was a little more differentiated from some of the other molecules that we have seen. That’s all I could say. 谢谢你，杰夫。埃文，感谢你的提问。关于临床前数据，我要说的是，当我最初审视这个项目时，正是 707 或 4404 独特的四价结构——即四价抗体——吸引了我的注意。这种四价结构使每个臂能够同时结合 PD-1 和 VEGF。 在 VEGF 存在下，707 会形成多聚体——我们称之为"串联连接"的现象——从而显著增强对 PD-1 的亲和力，最终使 PD-1 结合能力提升近 10 倍。 该分子上完全功能化的 VEGF 臂设计尤为精妙——它既能驱动血管生成与抗血管生成，又能在肿瘤微环境中营造免疫抑制氛围。所有这些临床前数据都让我们对其青睐有加。其 VEGF 抑制机制相较其他分子更具差异化优势，以上便是我的全部说明。 The second piece of this question that you had was how are we differentiating from some of the data that we saw at ESMO this Ser? And I’m guessing you’re referring to the Harmony 6 study in squamous non-small lung cancer where was combined with chemotherapy combined – versus Pembro plus chemotherapy. And what I’ll tell you is that in our 98 -we had 125 patients treated with squamous non-small cell lung cancer, 98 of those patients were treated at the 10 mg per kg Q3 week FDA aligned those now. 您第二个问题是：我们如何与欧洲肿瘤内科学会（ESMO）会议上展示的部分数据区分开来？我猜您指的是鳞状非小细胞肺癌的 Harmony 6 研究——该研究将联合化疗与 Pembro 联合化疗进行对比。 我需要说明的是：在我们的 98 例患者中，共有 125 例鳞状非小细胞肺癌患者接受治疗，其中 98 例采用每公斤体重 10 毫克、每 3 周给药一次的方案——该剂量现已获得 FDA 批准。 And when we compare our small data set with the 260-some patients in the Harmony-6 arm, you can see that the overall response rate and is similar in terms of the – it’s very similar – our follow-up is – needs to be longer because we are a little slower – I mean, they’re further ahead in development. But when it comes to the toxicities. It seems like the VEGF rated toxicities, the all-grade hemorrhage, hemoptysis, et cetera, a bit similar between the two arms. So as we kind of expand into a larger data sets, we expect that these will bear out, and we’ll see really good efficacy and toxicity with our molecule. 当我们将小样本数据与 Harmony-6 组的 260 余例患者进行对比时，可见总体缓解率相当接近——两者非常接近——我们的随访周期需要更长，因为进展稍慢——我是说他们的研发进度更领先。 但就毒性反应而言，两组在 VEGF 相关毒性（全等级出血、咯血等）方面表现相当。随着数据集规模扩大，我们预期这些结果将得到验证，并最终展现出我们分子药物在疗效与安全性方面的卓越表现。 Our next question comes from David Risinger with Leerink Partners. It’s Jason Jaw on for Dave. I have 2 questions, please. So first of all, following up on the differentiation of 4404, could you please provide a road map for potential validation of the superior efficacy and specifically key readouts to watch in coming years that establishes differentiation versus other bispecifics? And second, given private licensing agreement with 3sbio please remind us about the economics for Pfizer and 3 and how Pfizer will book financials on the income statement. 我是杰森·乔，代戴夫提问。我有两个问题。 首先，关于 4404 的差异化优势，能否提供验证其卓越疗效的路线图？特别是未来几年需重点关注哪些关键指标，以确立其相较于其他双特异性抗体的差异化优势？其次，鉴于与三生的私下许可协议，请重申该协议对辉瑞和3sbio的经济影响，以及辉瑞将在损益表中如何核算相关财务数据。 Jeff Legos Thanks for the question, Jason, and maybe I’ll start by addressing the first 1 and then maybe ask Francesca to come back in on the economics for the 3SBio deal. So first, you talked about the road map here. And I just want to remind the audience that this deal didn’t close until sort of late July, early August this year. And I am incredibly pleased and proud to wish to see that we were able to execute on a lot of the activities that we shared with you just over the past 3 months. 感谢你的提问，杰森。我先回答第一个问题，然后请弗朗西斯卡回来谈谈 3SBio 交易的经济层面。首先，你提到这里的路标。 需要提醒各位，这笔交易直至今年七月底八月初才最终完成。我深感欣慰与自豪的是，过去三个月里我们已成功推进了与各位分享的诸多工作事项。 And if we think about what has been accomplished by then, we were able to sort of transfer all of the data from our colleagues at 3SBio prepare these 7 regulator documents filed 5 INDs and now are well equipped to have these 7 near-term study starts, not to mention the tech transfer and the ability to sort of complete the first drug product manufacturing here in the United States. 若回顾迄今取得的进展，我们已成功将 3SBio 团队的所有数据完成转移，准备了 7 份监管文件，提交了 5 份 IND 申请，现已具备启动这 7 项近期研究的充分条件。更不用说技术转移的推进，以及在美国本土完成首款药品生产的能力。 So the first part of the road map is, obviously, the 7 near-term study starts that we’ve highlighted today. In terms of data readouts, we will continue to follow the additional patients for both depth and durability from the ongoing Phase II trials that 3SBio has already started. 路线图的第一部分显然是今天重点介绍的 7 项近期启动的研究。在数据解读方面，我们将持续追踪 3SBio 已启动的在研 II 期试验中新增患者的数据，重点关注疗效深度和持久性。 The next part of our road map, as mentioned during the presentation, it is up to 10 additional trials starting in 2026 and up to 10 additional novel combinations starting in 2026. So continuing to build upon the momentum that we’ve already started just over the previous 3 months. 正如演示文稿中所述，我们路线图的下一阶段计划于 2026 年启动多达 10 项新增临床试验，并同步推进多达 10 种创新组合方案的研发。这将延续过去三个月来我们已然形成的研发势头。 If we think about the kind of the overall trial readouts, most of these studies are Phase III studies with time-to-event endpoints of progression-free survival and overall survival. So I will just refer you to clinicaltrials.gov and look at the primary completion date as to when you could expect this data to become available. And maybe to your second question on the overall file economics and/or deal terms. Maybe I can invite Francesca to speak on that. 若从整体试验数据的角度考量，多数研究属于 III 期试验，其时间事件终点指标为无进展生存期和总生存期。因此建议您查阅 clinicaltrials.gov 网站，通过主要完成日期了解数据何时可供获取。至于您关于整体文件经济性及/或交易条款的第二个问题，或许可以请 Francesca 来阐述。 Francesca DeMartino Chief Investor Relations Officer Yes, I can take it, Jeff. Okay. So thanks for the question. So this is a pretty traditional structure. So they’re eligible to receive milestone payments associated with certain development, regulatory and commercial milestones. I think those were all disclosed upfront. And – yes, so that’s pretty much the structure. So there’s also tiered double-digit royalties on sales of 707, which we’re now calling 4404. So if you want to reference, I think we disclosed those all in the initial press release, pretty structure. 是的，我能理解，杰夫。好的。感谢提问。这其实是相当传统的结构。他们有资格获得与特定研发、监管及商业里程碑相关的付款。 这些条款均已事先披露。是的，基本架构就是如此。此外，针对 707（现更名为 4404）的销售额还设有阶梯式两位数专利使用费。如需查阅，我认为我们在最初的新闻稿中已完整披露了这些条款，架构相当清晰。 I think we’re actually, Jeff, I can close it because I think we’re – that was – no, there’s 1 more, I apologize if you just saw in the queue. 杰夫，我觉得我们可以结束了，因为我认为——那件事——不，还有一件事，如果你刚好看到队列里的内容，我在此致歉。 We’ll go next to Chris Schott with JPMorgan. 接下来请摩根大通的克里斯·肖特提问。 Ethan Brown JPMorgan Chase & Co This is Ethan on for Chris Schott. Just maybe broadly, can you talk about how you think about the relative opportunities with 4404 either alone or in combo with chemo versus kind of the opportunities you have in combination with our ADCs and kind of in the context of increased competition with summit? 我是 Ethan，代 Chris Schott 发言。能否请您大致谈谈：您如何看待 4404 单独使用或与化疗联合使用的相对机遇？以及在与summit竞争加剧的背景下，您认为其与我们抗体药物偶联物（ADC）联合使用的机遇如何？ Jeff Legos Yes. Thanks for the question, Ethan. And I’m happy to start just with a broad and I’ll pass it over to Johanna. So as mentioned earlier, for both non-small cell lung cancer and colorectal cancer, despite the progress with chemotherapy plus or minus immunotherapy in lung cancer plus or minus bevacizumab in colorectal cancer. Both of these represent a significant unmet medical need. And both of these represents a pretty rapid path to the initial approvals and development because they are simple add-on trial designs. 是的。感谢你的提问，伊桑。我先从宏观层面谈谈，然后再请约翰娜补充说明。正如之前提到的，无论是非小细胞肺癌还是结直肠癌，尽管在肺癌领域已取得化疗联合免疫治疗（或联合贝伐珠单抗）的进展，在结直肠癌领域也取得类似进展，但这两种癌症仍存在显著的未满足医疗需求。 由于采用的是简单附加试验设计，这两类疾病都为药物研发提供了相当快速的初始审批和开发路径。 So you’re combining on top of the standard of care to hopefully improve displays or replace the existing chemotherapy regimens and/or in combination with 4404. As we think about the novel combinations, this is where the breadth and the depth of our portfolio represents a significant and unique opportunity for us to differentiate. So maybe, John, I’ll turn it over to you to share a little bit more as to how you’re thinking about the next wave of opportunities. 因此，您是在现有治疗标准基础上进行组合，旨在优化疗效或替代现有化疗方案，并可与 4404 联合使用。当我们探讨创新组合方案时，正是我们产品组合的广度与深度为我们提供了显著且独特的差异化机遇。约翰，或许现在可以请您分享更多关于如何把握下一波机遇的思考。 Johanna Bendell Chief Development Officer of Oncology Thanks so much, Jeff, and thanks so much for the question. I think 1 thing we’re particularly proud of at Pfizer in terms of our antibody drug conjugates is data that we’ve seen combining the Vedotin antibody drug conjugates with immune checkpoint inhibitors. We’ve already seen proof of this in the combination with our molecule and pembrolizumab, where we see improvement in the immunogenic potential of a PD-1 inhibitor, particularly when combined with a Vedotin payload rather than a TIVO-1 payload. So we’re hoping to not only take advantage of that vedotin ADC, but also with our novel targets for the vedotin ADCs such as integrated [ integrin beta-6] with our SP molecule and PD-L1 with our PD-L1b molecule. We also see across the spectrum of different tumor types areas for both anti-angiogenic approaches and immunotherapy approaches work. And we’re very excited for this molecule because we think that we have the potential to improve hitting both of these pathways and so as we start to think about the broad potential of these molecules being able to hit both of these pathways harder and potentially with less toxicity, we can think about a lot of different tumor types that could potentially benefit from this, not only in combination with our vedotin ADCs, but also in combination with other treatments such as the standard of care that Jeff was alluding to as well as potentially with single agent. 非常感谢杰夫，也非常感谢您的提问。在抗体药物偶联物领域，辉瑞尤其引以为豪的一点是：我们观察到维多汀抗体药物偶联物与免疫检查点抑制剂联合使用的数据。 我们已通过和派姆单抗的联合用药验证了这一效果：当维多汀载药分子替代 TIVO-1 载药分子时，PD-1 抑制剂的免疫原性潜力显著提升。 因此我们不仅希望利用维多汀 ADC 的优势，还计划开发新型靶向维多汀 ADC 的靶点，例如整合[整合素β6]与 SP 分子、PD-L1 与 PD-L1b 分子。 我们还发现，在不同肿瘤类型的谱系中，抗血管生成疗法和免疫疗法都存在发挥作用的空间。我们对这种分子充满期待，因为我们认为它有潜力同时增强这两条通路的靶向效果。随着我们开始思考这些分子在更强效作用于这两条通路的同时可能降低毒性的广泛潜力， 不仅能与我们的维多汀抗体药物偶联物联合使用，还可与其他治疗方案（如杰夫提及的标准疗法）联合应用，甚至可能作为单药治疗，为多种肿瘤类型带来潜在获益。 Francesca DeMartino Chief Investor Relations Officer Okay. Great. Jeff, that was our last question. So I will – I just want to thank Jeff, Johanna and Arati again, for joining us this morning. This is a really comprehensive overview. And for those of you that have dialed in and our sell-side analysts, thank you so much for your time and your engagement and I hope everybody has a wonderful week and we will see you and talk to you soon. Everyone can disconnect. Thank you so much. 好的，太好了。杰夫，这是我们最后一个问题。我谨再次感谢杰夫、约翰娜和阿拉蒂今天上午的参与。本次会议提供了非常全面的概述。感谢所有拨入会议的听众以及卖方分析师们拨冗参与并积极互动。祝大家本周一切顺利，我们很快再会。各位可以挂断电话了。非常感谢。